In diagnostic X-ray imaging, iodine compounds are frequently used as contrast enhancing agents. The compounds used for this purpose for the most part are compounds containing one or two triiodophenyl groups, and thus are often referred to respectively as monomers and dimers.
Examples of commercially available triiodophenyl monomers and dimers include the monomeric compounds acetrizoate, diatrizoate, diodone, iobenzamate, iocetamate, iodamide, iodohippurate, ioglicate, iopamoate, iophendylate, iopronate, iothalamate, oxitalamate, ipodate, metrizoate, iomeprol, iopentol, iopromide, iosimide, ioversol, ioglucol, iogluamide, ioglunide, iogulamide, iosarcol, ioxilan, metrizamide, iopamidol and iohexol, and the dimeric compounds iocarmate, iodipamide, iodoxamate, ioglycamate, ioxaglate, iotroxate, iotasul, iotrolan, iodecimol and iodixanol.
Other monomers and dimers are known from the literature and may be prepared in accordance with the present invention, for example the monomers and dimers referred to in WO-94/14478 (Bracco).
In the conventional processes used for the preparation of these compounds, iodination of the aromatic rings is generally the last or one of the last process steps as in this way utilization of the relatively expensive iodinating agents is optimised.
Thus, for example, in the production of iohexol or iodixanol, the iodination step is conventionally effected using the intermediate 3,5-bis(2,3-dihydroxypropylaminocarbonyl)-aniline.
The iodination reaction, serving to introduce iodines at all of the unsubstituted aromatic ring positions, is conventionally performed using ICl (or its iodide salt analogues such as KICl.sub.2 or NaICl.sub.2) in an acidic aqueous medium. Examples of such iodination reactions can be found for example in WO-92/14695 (Guerbet) and U.S. Pat. No. 5,013,865 (Mallinckrodt).
These ICl iodination agents are commercially available as corrosive aqueous solutions which have a limited storage life. Furthermore, in the iodination reaction some chlorination may occur as an undesired side-reaction.
Mono-iodination of aromatic species by a procedure known as electrochemical iodination, has been described for example by Shono et al in Tetrahedran Letters 13:1649-1650 (1989). This procedure involves anodic generation from an iodine source of iodide (I.sup.+) cations which react to substitute the aromatic ring of a target aromatic compound.
Shono et al (supra) and the other investigators of electrochemical iodination have only suggested its use for introducing a single iodine onto the aromatic ring of the target compound, generally with high paraposition specificity.
It has however now been found that triiodination of the monomeric intermediates and hexaiodination of the dimeric intermediates for the iodinated X-ray contrast agents can be effected in high yield by electrochemical iodination in an acidic solvent mixture which comprises water and optionally at least one water-miscible organic solvent, preferably a polar and/or protic solvent. This route allows the use of cheaper, non-corrosive and highly stable iodine sources (such as iodine and potassium iodide for example) and thus offers significant benefits in the commercial production of iodinated X-ray contrast agents.